Phenotypically distinct subsets of CD4<sup>+</sup> T cells induce or protect from chronic intestinal inflammation in C. B-17 <i>scid</i> mice

Powrie, Fiona; Leach, Michael W.; Mauze, Smita; Caddle, Linda Barcomb; Coffman, Robert L.

doi:10.1093/intimm/5.11.1461

Cited by 990 publications

(833 citation statements)

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“…This molecule is produced by P IEL, but does not appear to play an essential role in the regulatory process mediated by P IEL in this model system, since P IEL isolated from IL-10 -/-mice remain protective following transfer. Although CD4 + CD45RB low CD25 + T cells producing IL-10 have been implicated as T regulatory cells [25], the depletion of the CD25 + population in recipients of IEL has no effect on the protective capacity of P IEL against parasite challenge. Among the P IEL population, the CD8 § g subset, which has been revealed as the most protective [21], produced a greater amount of TGF-g compared with the CD8 § § subset.…”

Section: Discussionmentioning

confidence: 99%

Intestinal intraepithelial lymphocytes prevent pathogen‐driven inflammation and regulate the Smad/T‐bet pathway of lamina propria CD4⁺ T cells

et al. 2004

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Intraepithelial lymphocytes (IEL) play a key role in gut homeostasis and are critical effector cells preventing the inflammatory intestinal lesions induced in mice following oral infection with Toxoplasma gondii. In this intestinal inflammatory model, CD4 + T lymphocytes from the lamina propria (LP) synergize with the infected enterocytes to secrete pro-inflammatory chemokines and cytokines. In this study, we assessed the mechanisms accounting for the ability of IEL to modulate the inflammatory activity of these cells. Adoptive transfer of IEL purified from wild-type mice, or CD154-,CD95L-or IL-10-deficient mice infected with T. gondii completely impairs the development of the lethal ileitis in recipient mice orally infected with T. gondii. Compared with unprimed IEL isolated from naive mice, the CD8 § g TCR § g subset of primed IEL, isolated from T. gondii-infected mice, secretes increased amount of TGF-g . IEL interact with the LP CD4 + T lymphocytes, down-regulate their production of inflammatory cytokines such as IFN-+ and reduce their proliferative activity. These effects are linked to the secretion of TGF-g and are correlated with a shift in the balance between Smad7/T-bet down-regulation and Smad2/Smad3 up-regulation in LP CD4 + T lymphocytes.

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Section: Discussionmentioning

confidence: 99%

Intestinal intraepithelial lymphocytes prevent pathogen‐driven inflammation and regulate the Smad/T‐bet pathway of lamina propria CD4⁺ T cells

et al. 2004

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“…To assess how the differential rate of AICD induction in wtTNF and tmTNF CD4 1 T cells affects T-cell expansion during inflammatory conditions in vivo, we followed the accumulation of transferred T cells in the CD4 1 CD45RB hi T-cell transfer model of colitis [20,21]. To this end, colitogenic wtTNF and tmTNF CD4 1 T-cell subsets were adoptively transferred into wtTNF and tmTNF RAG2 À/À recipients, respectively.…”

Section: Accelerated Accumulation Of Tmtnf Cd4 1 T Cells In Tmtnf Ragmentioning

confidence: 99%

“…with 2 Â 10 5 sorted CD4 1 CD45RB hi splenocytes from wtTNF or tmTNF mice as described previously [45]. CD4 1 T cells that express high levels of CD45RB are generally considered naïve T cells and induce progressive colonic inflammation upon adoptive transfer in lymphopenic mice [20]. After 8 or 15 days post transfer, mice were euthanized and tissue samples removed for histological assessment of colonic inflammation, cell isolations, and functional assays.…”

Section: Assessment Of Functional Fas Expressionmentioning

confidence: 99%

Soluble TNF‐α but not transmembrane TNF‐α sensitizes T cells for enhanced activation‐induced cell death

et al. 2009

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In addition to its proinflammatory effects, TNF-a exhibits immunosuppression. Here, we compared the capacities of transmembrane TNF-a (tmTNF) and soluble TNF-a (sTNF) in regulating expansion of activated T cells by apoptosis. Splenic CD4 1 T cells from wtTNF, TNF-a-deficient (TNF À/À ) and TNF À/À mice expressing a non-cleavable mutant tmTNF showed comparable proliferation rates upon TCR-mediated stimulation. Activationinduced cell death (AICD), however, was significantly attenuated in tmTNF and TNF À/À , compared with wtTNF CD4 1 T cells. Addition of sTNF during initial priming was sufficient to enhance susceptibility to AICD in tmTNF and TNF À/À CD4 1 T cells to levels seen in wtTNF CD4 1 T cells, whereas addition of sTNF only during restimulation failed to enhance AICD. sTNF-induced, enhanced susceptibility to AICD was dependent on both TNF receptors. The reduced susceptibility of tmTNF CD4 1 T cells for AICD was also evident in an in vivo model of adoptively transferred CD4 1 T-cell-mediated colonic inflammation. Hence, the presence of sTNF during T-cell priming may represent an important mechanism to sensitize activated T cells for apoptosis, thereby attenuating the extent and duration of T-cell reactivities and subsequent T-cell-mediated, excessive inflammation.Key words: Activation-induced cell death . CD4 1 T cells . Colitis . TNF-a .Transmembrane TNF IntroductionTNF is a pleiotropic cytokine involved in innate and adaptive immunity. It is regarded as the prototypic proinflammatory cytokine and is crucial in immune defense against many pathogens but also during development of various autoimmune diseases [1]. The type I transmembrane 26 kDa precursor TNF molecule (tmTNF) is preferentially cleaved by the extracellular metalloproteinase TNF-a-converting-enzyme (TACE) to release trimers of the 17 kDa soluble form (sTNF) [2]. The generation of non-cleavable mutants of TNF revealed that tmTNF and sTNF exert distinct biological functions. A main function ascribed to tmTNF is the induction of cell death [3]. Some of the proinflammatory effects ascribed to TNF are also mediated by tmTNF as shown by the tmTNF-induced up-regulation of ICAM-1 and VCAM-1 on endothelial cells in vitro [4]. Mice overexpressing a non-cleavable tmTNF mutein are prone to develop arthritis [5] and signs of hepatitis after Concanavalin A (Con A) administration [6]. tmTNF transgenic mice [4] and tmTNF knock-in mice [7] are, in contrast to wtTNF mice, protected from LPS-induced death, thus demonstrating the distinct roles exerted by tmTNF and secreted TNF. Treatment of mice with a synthetic TACE inhibitor also protects mice from endotoxin-mediated death [8], indicating that TACE may represent a target to prevent the fatal effects of excessive sTNF production while maintaining the local TNF-mediated effects required in the host response against intracellular pathogens. The fact that tmTNF mice, but not TNF-deficient mice, are still capable of forming granulomas following infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG) and thu...

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“…Transfer of naïve CD4 + CD45RB high T cells into immunodeficient mice such as SCID or RAG-/-results in colitis driven by Th1 cytokines [10], which can be abrogated by co-transfer of CD4 + CD25 hi CD45RB lo regulatory T cells (Tr) [11]. Additional subsets of regulatory T cells such as Tr1 cells producing high amounts of Il-10 or Th3 cells producing TGF-b have also been described.…”

Section: Immunopathogenesis Of Inflammatory Bowel Diseasementioning

confidence: 99%

Therapeutic targeting of α4-integrins in chronic inflammatory diseases: tipping the scales of risk towards benefit?

Engelhardt

Briskin

2005

Eur. J. Immunol.

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Inhibition of leukocyte trafficking via a4-integrin antibody blockade has recently become a validated therapeutic approach for several inflammatory diseases, including multiple sclerosis, ulcerative colitis and Crohn's disease. In the midst of this recent success, 3 patients receiving chronic treatment with the anti-a4 antagonist natalizumab (Tysabri) for the treatment of multiple sclerosis or Crohn's disease, developed JC-virus related progressive multifocal leukoencephalopathy (PML). These unforeseen consequences suggest that long term blockade of a4-integrins might prevent trafficking of non-pathogenic lymphocytes that are essential for viral immunosurveillance. In the current issue of the European Journal of Immunology Bjursten and colleagues report that long term treatment with anti-a4-integrin antibodies results in exacerbation of the murine model of colitis induced by the targeted deletion of the heterotrimeric G protein subunit Gai2. In order to properly evaluate the efficacy and safety of anti-a4-integrin therapy, the relationship between these observations in an immunologically altered animal model and human clinical disease needs to be carefully measured.

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Phenotypically distinct subsets of CD4⁺ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice

Cited by 990 publications

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Intestinal intraepithelial lymphocytes prevent pathogen‐driven inflammation and regulate the Smad/T‐bet pathway of lamina propria CD4⁺ T cells

Intestinal intraepithelial lymphocytes prevent pathogen‐driven inflammation and regulate the Smad/T‐bet pathway of lamina propria CD4⁺ T cells

Soluble TNF‐α but not transmembrane TNF‐α sensitizes T cells for enhanced activation‐induced cell death

Therapeutic targeting of α4-integrins in chronic inflammatory diseases: tipping the scales of risk towards benefit?

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Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice

Cited by 990 publications

References 0 publications

Intestinal intraepithelial lymphocytes prevent pathogen‐driven inflammation and regulate the Smad/T‐bet pathway of lamina propria CD4+ T cells

Intestinal intraepithelial lymphocytes prevent pathogen‐driven inflammation and regulate the Smad/T‐bet pathway of lamina propria CD4+ T cells

Soluble TNF‐α but not transmembrane TNF‐α sensitizes T cells for enhanced activation‐induced cell death

Therapeutic targeting of α4-integrins in chronic inflammatory diseases: tipping the scales of risk towards benefit?

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Phenotypically distinct subsets of CD4⁺ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice

Intestinal intraepithelial lymphocytes prevent pathogen‐driven inflammation and regulate the Smad/T‐bet pathway of lamina propria CD4⁺ T cells

Intestinal intraepithelial lymphocytes prevent pathogen‐driven inflammation and regulate the Smad/T‐bet pathway of lamina propria CD4⁺ T cells